Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin

Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues. [Display omitted] •Cell states marked by chromatin and gene expression are correlated but distinct•Lineage-determining genes are marked by domains of regulatory chromatin (DORCs)•DORCs are accessible prior to gene expression, foreshadowing lineage choice•Chromatin accessibility lineage-priming predicts cell fate decisions SHARE-seq, a highly scalable approach to measure chromatin accessibility and gene expression in the same single cell, links distal regulatory elements to key lineage-specifying genes and finds that chromatin accessibility foreshadows gene expression.